1. Field of the Invention
This application relates to circadian rhythms in humans, and particularly to the synchronization of such human circadian rhythms with the external environment. Specifically, this invention describes methods for achieving a chronobiologic (circadian phase-shifting) effect in humans. The invention provides methods to specifically advance or delay the phase of certain circadian rhythms in humans. Specific embodiments of the invention comprise methods for alleviating the effects of transmeridional travel (i.e., jet lag); methods for alleviating certain circadian phase disturbance-based psychopathological disorders such as winter depression (or seasonal affective disorder); methods for achieving synchrony between a human""s wake/sleep cycle or other circadian rhythms and the human""s occupational and other human activity schedules; and methods for achieving synchrony between a human""s wake/sleep cycle and other circadian rhythms.
2. Background of the Related Art
The phenomenon of circadian rhythms in biology is well known, and circadian rhythms are exhibited by all eukaryotic plants and animals, including man. Biological rhythms are periodic fluctuations in biological properties over time; these include circadian as well as seasonal variations. Circadian, or approximately 24-hour, rhythms include the production of biological molecules such as hormones, the regulation of body temperature, and behaviors such as wakefulness, sleep and periods of activity.
In nature, circadian rhythms are closely tied to environmental cues that impose a 24-hour pattern on many of these fluctuations. When these cues are absent, most circadian rhythms have a periodicity different (in humans, usually slightly greater) than 24 hours. Circadian rhythms that are no longer regulated by environmental cues are said to be free running. The regulation of circadian rhythms by signals from the environment is said to involve entrainment of circadian rhythms. The environmental signals that affect entrainment have been termed zeitgebers, an example of which is the light/dark cycle.
It is thought in this art that the control of circadian rhythms in mammals is mediated by a portion of the brain called the superchiasmatic nuclei (SCN). Circadian rhythms are primarily entrained by the light and dark cycle; light signals are conveyed by the retina to the SCN, and the pineal gland, which is regulated by the SCN, produces melatonin (N-acetyl-5-methoxytryptamine).
Disruption of circadian rhythms can result in a number of pathophysiological states in humans; one of the most common of these is jet lag. The use of melatonin to ameliorate the effects of jet lag has been described in the prior art.
U.S. Pat. Nos. 4,665,086 and 4,600,723 teach the use of melatonin to alleviate the symptoms of jet lag. These patents teach the use of  greater than 1 to 10 mg of melatonin, taken at destination bedtime, and again upon premature awakening in the middle of the night.
Gwinner and Benzinger, 1978, J. Comp. Physiol. 126: 123-129 teach that daily injections of melatonin can entrain the activity/rest cycle in birds.
Arendt et al., 1984, Neurosci. Lett. 45: 317-325 and Arendt et al., 1985, CIBA Found. Symp. 117: 266-283 disclose that melatoriin in high doses increases tiredness and the tendency to sleep in humans.
Underwood, 1986, J. Pineal Res. 3: 187-196 discloses a phase response curve for melatonin in the lizard Sceloporus occidentalis. 
Arendt et al., 1987, Ergonomics 30: 1379-1393 disclose the administration of melatonin to alleviate jet lag by oral administration of exogenous melatonin 4 to 6 hours prior to the human""s normal bedtime.
Mallo et al. 1988, Acta Endocrinol. 119: 474-480 teach that the administration of 8 mg of melatonin to humans, one hour before bedtime over a course of four days, results in a slight phase advance in the melatonin rhythm three days after cessation of the melatonin treatment but not in other circadian rhythms.
Armstrong et al., 1989, Experientia 45: 932-938 disclose the effects of exogenous melatonin administration on the circadian rhythm of the sleep/wake cycle in rats, and that the effect was greatest when exogenous melatonin was administered a few hours before the effective start of the nocturnal activity cycle.
Petrie et al., 1989, Brit. Med. J. 298: 705-707 teach the administration of 5 mg of melatonin to humans on a schedule of three days before flight, during flight, and once a day for three days after arrival to alleviate jet lag caused by flights from Auckland, New Zealand to London and back.
Skene et al., 1989, Sleep ""88 (J. Horne, ed.), pp. 39-41 teach the use of melatonin to treat jet lag.
Sack and Lewy, 1989, Amer. Coll. Neuropsychopharm. Abstract suggest the possibility of achieving a phase advance in a human using melatonin administered in the evening.
Samel et al., 1991, J. Biol. Rhythms 6: 235-248 teach the use of melatonin for the treatment of jet lag using an administration schedule of melatonin administration at 1800 local time for 3 days before the time shift, and at 1400 local time for 4 days afterwards.
Nichelsen et al., 1991, Adv. Pineal Res. 5: 303-306 teach the administration of 5 mg melatonin at destination bedtime for the treatment of jet lag resulting from 6, 9 and 11 hour time-shifts.
Dahlitz et al., 1991, The Lancet 337: 1121-1124 disclosethe use of melatonin to treat delayed sleep phase disorder.
Claustrat et al., 1992, Biol. Psychiatry 32: 705-711 teach the use of melatonin to affect circadian rhythms.
Sack et al., 1994, Sleep Research 23: 509 disclose melatonin administration to promote adaptation to shift work.
Zaidan et al., 1994, Neuroendocrinol. 60: 105-112 describe a melatonin phase response curve.
Deacon and Arendt, 1995, Brain Res. 688: 77-85 disclose dose-dependent phase-shifting effects with melatonin administration.
U.S. Pat. No. 5,449,683 issued Sep. 12, 1995 to Wurtman teaches the use of low dose melatonin formulations to induce sleep.
U.S. Pat. No. 5,498,423, issued Mar. 12, 1996 to Zisapel, teaches melatonin administration in formulations provided to mimic a human""s endogenous nighttime melatonin profile.
Similarly, inhibition of endogenous melatonin production (using, for example, beta-blockers) for affecting human circadian rhythms have been reported in the prior art.
Schlager et al., 1993, Soc. Light Treat. Biol. Rhythms Abstracts 5: 23 teach early morning administration of short-acting beta-blockers for treatment of winter depression.
Schlager, 1994, Amer. J. Psych. 151: 1383-1385 teach early morning administration of short-acting beta-blockers for treatment of winter depression.
Schlager et al., 1996, Soc. Light Treat. Biol. Rhythms Abstracts #15 teach early morning administration of short-acting beta-blockers for treatment of winter depression.
The use of light to entrain circadian rhythms is known in the prior art.
Lewy et al, 1983, Psychopharmacol. Bull. 19: 523-525 disclose a phase response curve to light in humans and bright light treatment of delayed sleep phase syndrome.
Waver et al., 1983, Eur. J. Physiol. 396: 85-87 disclose light for resetting human temperature and activity rhythms.
Daan and Lewy, 1984, Psychopharmacol. Bull. 20: 566-568 disclose a phase response curve to light in humans and treatment of jet lag by scheduled exposure to light.
Lewy et al, 1985, in Photoperiodism, Melatonin and the Pineal Gland (Evered et al., eds.), pp. 231-252 disclose bright light treatment of advanced sleep phase syndrome.
Czeisler et al., 1986, Science 233: 667-671 disclose light for resetting the circadian rhythm pacemaker.
Lewy et al, 1987, Science 235:352-354 disclose circadian phase-shifting and antidepressant effects of light treatment
Eastman, 1987, Temporal Disorder in Human Oscillatory Systems, (Rensing et al., eds.) discloses light to promote adaptation to shift work.
Honma and Honma, 1988, Jap. J. Psychiatry Neurol. 42: 167-168 disclose a light phase response curve in humans.
Wever, 1989, J. Biol. Rhythms 4: 161-186 disclose a light phase response curve in humans.
Czeisler et al., 1989, Science 244:-1328-1333 disclose a light phase response curve in humans.
Hoban et al, 1989, Chronobiol. Intl. 6: 347-353 disclose the use of bright light treatment upon awakening to entrain a single sighted subject""s circadian rhythm.
Minors et al., 1991, Neurosci. Lett. 133: 36-40 disclose a light phase response curve in humans.
U.S. Pat. No. 5,163,426, issued Nov. 17, 1992 to Czeisler et al., discloses the use of bright light to affect circadian rhythms.
U.S. Pat. No. 5,167,228, issued Dec. 1, 1992 to Czeisler et al., discloses the use of bright light to affect circadian rhythms.
U.S. Pat. No. 5,176,133, issued Jan. 5, 1993 to Czeisler et al., discloses the use of bright light to affect circadian rhythms.
U.S. Pat. No. 5,304,212, issued Apr. 19, 1994 to Czeisler et al., discloses the use of bright light to affect circadian rhythms.
Eastman et al., 1994, Sleep 17: 535-543 disclose light exposure regulatory regimens for promoting adaptation to shift work.
McArthur et al, 1996, Sleep 19: 544-553 disclose the use of melatonin to entrain human circadian rhythms.
U.S. Pat. No. 5,503,637, issued Apr. 2, 1996 to Kyricos et al., disclose an apparatus for delivering bright light to a human to affect circadian rhythms.
U.S. Pat. No. 5,545,192, issued Aug. 13, 1996 to Czeisler et al., disclose the use of bright light to affect circadian rhythms.
Entrainment and regulation of circadian rhythms have been demonstrated in a number of animal species. The ability to effect an actual change in the phase of circadian rhythms would be useful for the alleviation of a number of circadian-rhythm related disorders.
U.S. Pat. No. 5,242,941, issued Sep. 7, 1993 and U.S. Pat. No. 5,420,152, issued May 30, 1995, both issued to the present inventors, were the first to disclose a phase response curve for melatonin in humans. These references taught that an appropriate time to administer melatonin to induce a change in phase of human circadian rhythms is related to the time of dim light melatonin onset (DLMO), a robust marker of a human""s circadian rhythms. Contrary to the teachings of the prior art (that melatonin was simply associated with darkness, which came to be thought of as being equivalent to sleep in diurnal animals), the teachings of these patents established that the circadian rhythm of endogenous melatonin production was tightly coupled to the endogenous circadian pacemaker that regulates the timing of a variety of other human circadian rhythms (such as core body temperature, cortisol and sleep propensity), and that affecting the phase of the human melatonin circadian rhythm by administration of exogenous melatonin could effect both phase advances and phase delays in other human circadian rhythms. These patents disclosed that the magnitude and direction (i.e., phase advance or phase delay) of the desired circadian rhythm phase shift was dependent on the time of melatonin administration. Contrary to the established teachings of the prior art, these patents prescribed administration of relatively non-soporific ( less than 1 mg) dosages of melatonin at times that usually were not equivalent to destination bedtime, based on the human melatonin phase response curve (PRC). The teachings of these patents are hereby expressly incorporated by reference.
U.S. Pat. No. 5,591,768, issued Jan. 7, 1997 to the present inventors, disclosed methods of administering exogenous melatonin at different clock times over a course of melatonin treatment, wherein melatonin administration was kept at a constant time relative to the dim light melatonin onset (DLMO) time. In this patent, the present inventors disclosed the use of administration regimes holding the time of melatonin administration constant relative to DLMO time for achieving both phase advances and phase delays of the melatonin phase response curve, for alleviating circadian rhythm disorders including jet lag, winter depression, shift work desynchronies, and sleep disorders. The teachings of this patent are hereby expressly incorporated by reference.
The human melatonin PRC described in U.S. Pat. Nos. 5,242,941 and 5,420,152 suggested that exogenous melatonin would be most effective when administered during the light period, to compete with light as a xe2x80x9csubstitutexe2x80x9d for darkness. The human melatonin PRC clearly shows that melatonin acts like darkness on the endogenous circadian pacemaker(s) in humans. The circadian rhythm of melatonin production has an active phase of about 12 hours (levels reaching from a few picograms per mL of plasma to as great as several hundred picograms per mL, depending on the individual) and a quiescent phase of about 12 hours (levels falling to about 10 pg/mL or lower, depending on the individual and sensitivity of the melatonin assay). In entrained, sighted individuals, melatonin is produced only during nighttime darkness and not during daytime darkness, suggesting that melatonin may act by helping the endogenous circadian pacemaker to discriminate between the nighttime dark period and sporadic episodes of daytime darkness (including daytime sleep). Melatonin in combination with dim light or darkness thus might be a more effective darkness zeitgeber than darkness alone in the absence of melatonin. Aside from its effect on causing the human to perceive darkness, sleep alone has been found to have little, if any, chronobiologic effect in humans; however, it is possible that sleep may have a slight effect in potentiating the phase-shifting effects of melatonin and darkness.
This invention relates to a method for achieving a chronobiologic (phase-shifting) effect in a human by regulation of a human""s circadian rhythms. Specifically, the circadian phase-shifting effect is achieved by the administration of exogenous melatonin. The methods of the invention produce phase shifting of circadian rhythms by administration of exogenous melatonin, wherein the term xe2x80x9cmelatoninxe2x80x9d is intended to encompass melatonin itself and other circadian rhythm phase-shifting compounds that increase-endogenous melatonin levels or act on melatonin receptors, the term xe2x80x9cmelatonin levelsxe2x80x9d is intended to encompass levels, particularly plasma concentration levels, of melatonin itself and melatonin agonists, and the term xe2x80x9cquiescent melatonin levelsxe2x80x9d is intended to encompass melatonin itself and equivalent agonists, as all of these terms are described herein (see the Detailed Description of Preferred Embodiments). Further, the methods of the invention relate to the timing of melatonin administration to the human. The methods described herein are used to advance or delay the phase of circadian rhythms in a human. This effect is advantageously achieved by administering exogenous melatonin to the human at an appropriate time relative to the human""s endogenous melatonin onset and offset times. In this way, the present invention is able to alleviate jet lag and other circadian rhythm disorders of both the phase-delay and the phase-advance types.
In one aspect of the invention is provided a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising administering to the human an amount of melatonin, said administration producing in the human a plasma melatonin concentration of greater than quiescent melatonin levels. The timing of plasma melatonin concentrations greater than quiescent melatonin levels overlaps with either the onset of endogenous melatonin production in the human (to cause a phase advance) or the offset of endogenous melatonin production in the human (to cause a phase delay). Thus, in one embodiment of the invention is provided a method for causing a circadian rhythm phase-shifting effect that is a phase advance, wherein the time of plasma melatonin concentration of greater than quiescent melatonin levels overlaps with the onset of endogenous melatonin production in the human. In this embodiment, melatonin is administered to the human in an immediate-release formulation before about circadian time (CT) 14, preferably after about CT 6, and levels continue past the time of endogenous melatonin onset (CT 14 is the time of an individual""s dim light endogenous melatonin onset, termed DLMO, which is defined and described in detail herein). Alternatively, exogenous melatonin is administered to a human in a delayed-release formulation at a time wherein plasma melatonin concentration in the human is increased to greater than quiescent levels before about CT 14, preferably after about CT 6. Alternatively, exogenous melatonin is administered to a human in a sustained-release formulation before about CT 14, preferably in a formulation having a duration of less than about 12 hours, and preferably after about CT 6 to continue past the time of endogenous melatonin onset. According to the methods of the invention, the duration of the exogenous melatonin pulse, as defined herein, is sufficient to overlap the endogenous melatonin onset time for any of these different types of administered formulations, and preferably does not overlap the endogenous melatonin offset time.
In another embodiment, the invention provides a method for causing a circadian rhythm phase-shifting effect that is a phase delay, wherein the time of plasma melatonin concentration of greater than quiescent melatonin levels overlaps with the offset of endogenous melatonin production in the human. In a preferred embodiment, exogenous melatonin is administered to a human in an immediate-release formulation before about CT 1, preferably after about CT 18. Alternatively, exogenous melatonin is administered to a human in a delayed-release melatonin formulation at a time wherein plasma melatonin concentration in the human is increased to greater than quiescent levels before about CT 1 preferably after about CT 18. Alternatively, exogenous melatonin is administered in a sustained-release formulation before about CT 1, preferably in a formulation having a duration of less than about 19 hours, and preferably at about CT 18, wherein the plasma melatonin concentration returns to quiescent levels before the next night""s endogenous melatonin onset. According to the methods of the invention, the duration of the exogenous melatonin pulse, as defined herein, is sufficient to overlap the endogenous melatonin offset time (typically, from CT 0 to CT 1) for any of these different types of administered formulations and preferably does not overlap the endogenous melatonin onset time.
In another aspect, the invention provides a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising administering to the human an amount of melatonin wherein said administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels for a duration that coincides at least in part with either the phase advance zone (about CT 6 to about CT 18) or phase delay zone (about CT 18 to about CT 6) of the human melatonin phase response curve. In a first embodiment of this aspect of the invention, the circadian rhythm phase-shifting effect is a phase advance and exogenous melatonin is administered in a formulation having a duration to provide a period of plasma melatonin concentration greater than quiescent melatonin levels within the interval from about CT 6 to about CT 18. In a second embodiment of this aspect of the invention, the circadian rhythm phase-shifting effect is a phase delay and exogenous melatonin is administered in a formulation having a duration to provide a period of plasma melatonin concentration greater than quiescent levels within the interval from about CT 18 to about CT 6. Melatonin administration for achieving a phase advance advantageously is performed using a melatonin formulation having a duration of elevated plasma melatonin concentration that provides maximum stimulation of the phase-advance portion of the phase response curve (about CT 6 to about CT 18) while avoiding stimulation of the phase-delay portion of the phase response curve (about CT 18 to about CT 6), that is, having a maximum duration of about 12 hours. Melatonin administration for achieving a phase delay advantageously is performed using, a melatonin formulation having a duration of elevated plasma-melatonin concentration that provides maximum stimulation of the phase-delay portion of the phase response curve (about CT 18 to about CT 6) while avoiding stimulation of the phase-advance portion of the phase response curve (about CT 6 to about CT 18). However, it is also advantageous both to stimulate the maximum amount of the phase-delay portion of the phase response curve, and to provide for the longest duration of elevated plasma melatonin concentration after the endogenous melatonin offset (at about CT 1) without overlapping the time of endogenous melatonin onset. Thus, for achieving a phase delay, melatonin is advantageously administered having a maximum duration of about 19 hours (i.e., from about CT 18 to about CT 13). For phase advances, exogenous melatonin administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels for a time or in a concentration during a time interval from about CT 6 to about CT 18 that is greater than that produced during the time interval from about CT 18 to about CT 6. For phase delays, exogenous melatonin administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels for a time or in a concentration during a time interval from about CT 18 to about CT 6 that is greater than that produced during the time interval from about CT 6 to about CT 18.
The invention also provides a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising regulating exposure of the human to light, preferably sufficiently bright light to suppress endogenous melatonin production. In one embodiment of this aspect of the invention, the phase-shifting effect is a phase delay, the method comprising exposing the human to light for a time from about CT 6 to about CT 18. In a preferred embodiment, the human is subjected to light exposure at a time from about CT 14 to about CT 18. In another embodiment, the phase-shifting effect is a phase advance, and the method comprises subjecting the human to light exposure at a time from about CT 18 to about CT 6. In a preferred embodiment, the human is subjected to light exposure at a time from about CT 18 to about CT 1.
The invention also provides a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising regulating exposure of the human to light, wherein the human is subjected to darkness or dim light, or by limiting light exposure,for example, by prescribing the use of dark or red-colored goggles or other means to prevent a human from exposure to a light stimulus. In one embodiment of this aspect of the invention, the phase-shifting effect is a phase advance, the method comprising subjecting the human to darkness or dim light from about CT 6 to about CT 18. In a preferred embodiment, the human is subjected to darkness or dim light from about CT 14 to about CT 18. In another embodiment of this aspect, the invention provides a method for achieving a circadian rhythm phase delay, the method comprising regulating exposure of the human to darkness or dim light from about CT 18 to about CT 6. In a preferred embodiment, the human is subjected to darkness or dim light from about CT 18 to about CT 1.
Also contemplated as components of the methods of the instant invention are embodiments wherein melatonin administration is accompanied, either at times coincident with melatonin administration times by reducing exposure to artificial or natural light (i.e., providing darkness), or at appropriate times other than melatonin administration times, by exposure of a human to light, either artificial or naturally-occurring. Appropriate combinations of exogenous melatonin administration, dim light or bright light treatments are provided by this invention, as described more fully in the Examples below.
In another aspect of the invention is provided a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising administering to the human an amount of a melatonin antagonist or inverse agonist. In these embodiments of the methods of the invention, melatonin antagonist or inverse agonist is administered at a time to produce preferred stimulation of either the advance or delay zone of the melatonin PRC, or to provide an overlap between the time of plasma concentration levels of the melatonin antagonist or inverse agonist either the onset of endogenous melatonin production in the human (to cause a phase delay) or the offset of endogenous melatonin production in the human (to cause a phase advance).
Thus, in one embodiment of this aspect of the invention is provided a method for causing a circadian rhythm phase-shifting effect that is a phase delay, wherein the time of plasma concentration of the melatonin antagonist or inverse agonist overlaps with the onset of endogenous melatonin production in the human. In this embodiment, melatonin is administered to the human in an immediate-release formulation before about circadian time (CT) 14, preferably after about CT 6, and that levels continue past the time of endogenous melatonin onset. Alternatively, a melatonin antagonist or inverse agonists is administered to a human in a delayed-release formulation before about CT 1, preferably after about CT 6. Alternatively, melatonin antagonists or inverse agonists are administered to a human in a sustained-release formulation before about CT 14, preferably in a formulation having a duration of less than about 12 hours, and preferably after about CT 6 to continue past the time of endogenous melatonin offset. According to the methods of the invention, the duration of the pulse of melatonin antagonist or inverse agonist, as defined herein, is sufficient to overlap the endogenous melatonin onset time for any of these different types of administered formulations.
In another embodiment, the invention provides a method for causing a circadian rhythm phase-shifting effect that is a phase advance, wherein the time of plasma concentration of the melatonin antagonist or inverse agonist overlaps with the offset of endogenous melatonin production in the human. In a preferred embodiment, a melatonin antagonist or inverse agonist is administered to a human in an immediate-release formulation before about CT 1, preferably after about CT 18. Alternatively, melatonin antagonists or inverse agonists are administered to a human in a delayed-release melatonin formulation at a time before about CT 1, preferably after about CT 18. Alternatively, melatonin antagonists or inverse agonists are administered in a sustained-release formulation before about CT 1, preferably in a formulation having a duration of less than about 19 hours, and preferably after about CT 18, wherein the plasma concentration levels of melatonin antagonist or inverse agonist decrease to pre-treatment levels before the next night""s endogenous melatonin onset. According to the methods of the invention, the duration of the exogenous pulse of melatonin antagonist or inverse agonist, as defined herein, is sufficient to overlap the endogenous melatonin offset time (typically, from CT 0 to CT 1) for any of these different types of administered formulations and preferably does not overlap the endogenous melatonin onset time (DLMO).
In another embodiment of this aspect of the present invention, melatonin antagonist or inverse agonist is administered at a time wherein said administration produces in the human a plasma concentration of melatonin antagonist or inverse agonist for a time or in a concentration during a time interval from about CT 6 to about CT 18 that is greater than that produced during the time interval from about CT 18 to about CT 6, to provide a phase delay. For a phase advance, melatonin antagonist or inverse agonist is administered at a time wherein said administration produces in the human a plasma concentration of melatonin antagonist or inverse agonist for a time or in a concentration during a time interval from about CT 18 to about CT 6 that is greater than that produced during the time interval from about CT 6 to about CT 18, to produce a phase advance.
In another embodiment, the invention provides a method for achieving a circadian rhythm phase-shifting effect in a human, the method comprising administering to the human an amount of a compound that decreases endogenous production of melatonin in the human wherein said administration reduces endogenous plasma melatonin concentration in the human to a plasma concentration for a duration of time that is co-incident with a portion of the profile of endogenous melatonin production. In one embodiment of the method of the invention, the circadian rhythm phase-shifting effect is a phase advance and the duration of the effect of administration of a compound that decreases endogenous production of melatonin in the human on plasma melatonin concentration is from about CT 18 to about CT 1. In another embodiment, the circadian rhythm phase-shifting effect is a phase delay and the duration of the effect of administration a compound that decreases endogenous production of melatonin in the human on plasma melatonin concentration is from about CT 14 to about CT 18. In preferred embodiments, the administered melatonin reducing compound is a beta-blocker.
The invention also provides methods for administering melatonin to a human without causing a circadian rhythm phase-shifting effect. In this aspect, the invention provides a method of administering melatonin to a human without causing a phase shift in the human""s circadian rhythms. The inventive methods comprise administering melatonin to a human wherein said administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels wherein the duration of elevated plasma concentration greater than quiescent levels overlaps equally with both the onset time and offsef time of endogenous melatonin production in the human. In an alternative embodiment of this aspect of the invention, melatonin is administered wherein said administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels where in the duration of elevated plasma concentration coincides with equal portions of the phase advance and phase delay zones of the human""s phase response curve.
Thus, in one embodiment of this aspect of the invention is provided a method comprising the step of administering to the human melatonin wherein said administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels for a time wherein the rise of exogenous melatonin is about as many hours earlier than the onset as the fall of exogenous melatonin is later than the offset of the human""s pre-treatment endogenous melatonin profile. In another embodiment, the invention provides a method comprising administering to the human melatonin wherein said administration produces in the human a plasma melatonin concentration of greater than quiescent melatonin levels for a time wherein the time of plasma melatonin concentration levels of greater than quiescent melatonin levels is co-incident with an equal portion of the phase advance and the phase delay zones of the individual""s melatonin phase response curve.
Methods for administering melatonin antagonists, inverse agonists and compounds that reduce endogenous melatonin production in a human that do not produce a phase shift are also provided by the invention. In one embodiment of this aspect of the invention, the method comprises administering to the human a melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human, wherein said administration produces a plasma concentration of melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human for a time co-incident with equal portions of the phase advance and phase delay zones of the individual""s melatonin phase response curve. In another embodiment, the method comprises administering to the human a melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human, wherein said administration produces a plasma concentration of melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human for a time wherein the rise of plasma concentration of melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human is about as many hours earlier than the onset as the fall of plasma concentration of melatonin antagonist, inverse agonist or a compound that reduces melatonin production in a human is later than the offset of the human""s pre-treatment endogenous melatonin profile.
The methods of the invention are advantageously provided to alleviate a circadian rhythm-associated disorder in a human. In preferred embodiments, the circadian rhythm-associated disorder is jet lag, winter depression, shift-work related desynchronies or sleep disorders.
Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.